Prolonged-action eye drop

ABSTRACT

Eye drops containing a β-blocker such as cartelol hydrochloride are improved in the penetration of the β-blocker into the eye and the retention thereof in the eye tissues by the incorporation of a C 3-7  fatty acid such as sorbic acid to the eye preparations.

TECHNICAL FIELD

[0001] The present invention relates to an eye drop comprising aβ-blocker and a C₃-C₇ fatty acid or the salt thereof. Also, the presentinvention relates to a method to promote penetration of a β-blocker intothe eye and to improve the retention of the β-blocker in the oculartissues by incorporating a C₃-C₇ fatty acid or the salt thereof into aneye drop containing the β-blocker.

BACKGROUND OF THE INVENTION

[0002] Recently, the β-blockers, such as carteolol hydrochloride,timolol maleate, betaxolol hydrochloride and the like, are used as amedicine for glaucoma in the form of the eye drop. However, many of theactive components of the eye drops such as carteolol hydrochloride havehigh water-solubility, and in these cases, the highly hydrophobiccorneal epithelium becomes a barrier to the penetration of thecomponents into the eye. It is therefore necessary to instill the eyedrop containing the components in high dose or many times in order toget the sufficient amount of the components penetrated in the eyetissues for lowering an intraocular pressure. However, in order toseparate from the systemic effect of the β-blocker, to get more effecton lowering intraocular pressure and to get the prolonged-action of theβ-blocker, it is preferable to promote penetration of the drugs into theeye and to prolong retention of the drug in the eye than to instill ahigh dose of the eye drop and to instill many times.

[0003] From the above view point, it has been investigated to improvethe permeability of the β-blocker into cornea, and it is reported thatcapric acid (C₁₀ saturated fatty acid) promotes the permeability of theβ-blocker such as atenolol, carteolol, tilisolol and timolol into corneain vitro (H. Sasaki et al., Pharm. Research. 12(8), 1146-1150 (1995))and that the instillation of the eye drop containing ion pair ofcaprylic acid (C₈ saturated fatty acid) and timolol to a rabbitincreases the amount of timolol penetrated into aqueous humor (M. R.Gasco et al., J. Pharm. Biomed. Anal. 7, 433-439 (1989)). JP Patent No.2563336 also discloses that bunazosin hydrochloride of a sympathetic α₁receptor blocker can enhance the permeability into cornea byincorporating caproic acid, caprylic acid and capric acid (C₆-C₁₀ linearfatty acids).

[0004] However, in the prior art, it can not be found any data or anydescription showing that the retention time of the β-blocker or thesympathetic α₁ receptor blocker in the ocular tissues is prolonged, butonly the descriptions of the promotion of the drug penetration intocornea and the increase of the amount of the drug permeated in aqueoushumor.

[0005] On the other hand, sorbic acid of C₆ unsaturated fatty acid is acompound commonly used as a preservative of agents for a contact lensbecause of its becteriostatic effect. However, there is no reportshowing that the unsaturated fatty acid such as sorbic acid acceleratesthe penetration of the drugs into the eye by the instillation of the eyedrop, but on the contrary, there has been reported that the acid has noeffect on the corneal permeability of tilisolol of the β-blocker invitro (J. Pharm. Pharmacol. 47, 703-707 (1995)). There is also no priorart concerning the effect of the C₃-C₇ fatty acids on the cornealpermeability of the β-blocker.

DISCLOSURE OF THE INVENTION

[0006] The object of the present invention is to provide an eye dropcapable of promoting the penetration of a β-blocker such as carteololhydrochloride, timolol maleate and betaxolol hydrochloride, and toimprove the retention of the drug in the ocular tissues.

[0007] Herein, the penetration into the eye means that the drug afterthe instillation permeates into corneal epithelium and the like andpenetrates into the ocular tissues such as corneal stroma, aqueoushumor, iris and ciliary body, lens, vitreous body and retina.

[0008] As the results of the extensive studies by the present inventors,it was found that the sorbic acid which does not show any actionpromoting the permeation of the β-blocker into cornea in vitro promotesthe amount of penetration of the β-blocker in vivo and prolongs theretention period of β-blocker in the ocular tissues. Furthermore, it wasalso found that the C₃-C₇ fatty acid accelerates the penetration ofβ-blocker into the eye, thence the present invention was accomplished.

[0009] Namely, the present invention relates to

[0010] (1) an eye drop comprising a β-blocker and a C₃-C₇ fatty acid orthe salt thereof,

[0011] (2) the eye drop according to (1), wherein the β-blocker iscarteolol or the salt thereof,

[0012] (3) the eye drop according to (1), wherein the β-blocker istimolol or the salt thereof,

[0013] (4) the eye drop according to (1), wherein the β-blocker isbetaxolol or the salt thereof,

[0014] (5) the eye drop according to one of (1) to (4), wherein theC₃-C₇ fatty acid is an unsaturated fatty acid,

[0015] (6) the eye drop according to one of (1) to (5), wherein theC₃-C₇ fatty acid is a C₆ unsaturated fatty acid,

[0016] (7) the eye drop according to (6), wherein the C₆ unsaturatedfatty acid is sorbic acid,

[0017] (8) a method for promoting the penetration of a β-blocker intothe eye and improving the retention of the β-blocker in the oculartissues which comprises incorporating a C₃-C₇ fatty acid or the saltthereof into an eye drop containing the β-blocker.

[0018] As the β-blocker used for the eye drop of the present invention,for example, carteolol, timolol, betaxolol, befunolol, metipranolol,levobunolol and the like which are used as a medicine for glaucoma maybe used. Among them, carteolol, timolol and betaxolol may be usedpreferably.

[0019] As the pharmaceutically acceptable salt of the β-blocker used forthe eye drop of the present invention, there are exemplified by acidaddition salts such as hydrochloride, sulfate, nitrate, hydrobromide,hydroiodide, phosphate, acetate, maleate, fumarate, citrate andtartrate. Among the above salts, hydrochloride and maleate arepreferable.

[0020] The concentration of the β-blocker or the salt thereof(hereinafter, may be simply called as “the β-blocker”) used for the eyedrop of the present invention is different depending on the degree ofglaucoma, but may be usually about 0.02 to 3 w/v %, preferably about0.05 to 2 w/v %, more preferably about 0.1 to 2 w/v %.

[0021] The C₃-C₇ fatty acid (hereinafter, may be simply called as “thefatty acid”), preferably the C₄-C₆ fatty acid may be used for the eyedrop of the present invention. The fatty acid used in the presentinvention may be one of a straight or a branched and a saturated or anunsaturated monocarboxylic acid and dicarboxylic acid, preferablypropionic acid, butyric acid, isobutyric acid, valeric acid, pivalicacid, caproic acid, heptanoic acid, malonic acid, succinic acid,glutaric acid, adipic acid, pimelic acid, crotonic acid, sorbic acid,maleic acid, fumaric acid and the like, more preferably sorbic acid. Asthe salt of the fatty acid, there are exemplified by sodium salt,potassium salt and the like.

[0022] The concentration of the fatty acid or the salt thereof used forthe eye drop of the present invention is different depending on the kindof β-blocker, but may be usually about 0.01 to 10 w/v %, preferablyabout 0.02 to 5 w/v %, more preferably about 0.04 to 2 w/v %. In theratio of the fatty acid or the salt thereof to the β-blocker, the fattyacid or the salt thereof may be usually 0.01 to 10 weight ratio,preferably 0.05 to 3 weight ratio, more preferably 0.1 to 5 weightratio, relative to 1 weight of the β-blocker. Also, the ratio of thefatty acid or the salt thereof may be 0.2 to 5 moles, preferably 0.2 to2 moles, relative to 1 mole of carteolol hydrochloride, may be 0.2 to 10moles, preferably 1 to 5 moles, relative to 1 mole of timolol maleate,and may be 0.5 to 10 moles, preferably 2 to 5 moles, relative to 1 moleof betaxolol hydrochloride.

[0023] pH of the eye drop of the present invention may be adjustedusually to 4.5 to 8.5, preferably 5 to 8, more preferably 6 to 7.

[0024] To the eye drop of the present invention, additives usually usedfor the eye drop, for example, isotonic agents (sodium chloride,potassium chloride, glycerin, mannitol, sorbitol, boric acid, glucoseand propylene glycol, etc.), buffer (phosphate buffer, acetate buffer,borate buffer, carbonate buffer, citrate buffer, tris buffer, glutamicacid and ε-aminocaproic acid, etc.), preservatives (benzalkoniumchloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol,benzyl alcohol, sodium dehydroacetate, para-hydroxybenzoates, sodiumedetate and boric acid, etc.), stabilizers (sodium bisulfite, sodiumthiosulfate, sodium edetate, sodium citrate, ascorbic acid anddibutylhydroxytoluene, etc.), thickening agents (water-soluble cellulosederivatives such as methylcellulose, hydroxyethylcellulose,hydroxypropylmethylcellulose and carboxymethylcellulose; sodiumchondroitin sulfate, sodium hyaluronate, carboxyvinylpolymer, polyvinylalcohol, polyvinylpyrrolidone and macrogol, etc.), pH adjusters such ashydrochloric acid, sodium hydroxide, phosphoric acid and acetic acid maybe added, if desired. The amount of the additives is different dependingon the kind of the additives and the purpose thereof, but may be aconcentration capable of accomplishing the purpose thereof. The isotonicagents may be usually added in an amount to give 0.8 to 1.2 of theosmotic pressure ratio. The buffers may be added in an amount of about0.01 to 2 w/v %. The stabilizers may be added in an amount of about0.001 to 1 w/v %. And the thickening agents may be added in an amount ofabout 0.001 to 3 w/v %.

[0025] To the eye drop of the present invention, other pharmaceuticalcomponents other than the β-blocker may be appropriately added not sofar as the object of the present invention is deviated.

[0026] The eye drop of the present invention may be produced accordingto the usual method for producing the eye drop, for example, a methoddescribed in Ophthalmic Solutions of General Rules for Preparations (JP,13th edition).

[0027] Because the eye drop of the present invention promotes thepenetration of the β-blocker into the eye and improves the retention ofthe β-blocker in the ocular tissues, the frequency of the instillationcan be decreased and the bother in instilling many times can be avoided.The sufficient effect is obtained also when the incorporated amount ofthe drug is decreased. Concretely, for example, in case that the eyedrop containing carteolol hydrochloride 1 w/v % is used for the adultpatient suffering from glaucoma, it may be instilled once about 1 dropper 1 to 3 days, preferably once about 1 drop per 1 day. In case thattimolol maleate 0.68 w/v % (0.5 w/v % as timolol) is employed, the eyedrop may be instilled once about 1 drop per 1 day.

BRIEF EXPLANATION OF THE DRAWINGS

[0028]FIG. 1 is a graph showing the amount of carteolol hydrochloride inaqueous humor at the time of 1 hour after the instillation of the eyedrop (containing 2w/v % carteolol hydrochloride) of Example 1 in TestExample 1. The horizontal axis shows the test group and the verticalaxis shows the concentration of carteolol hydrochloride in aqueous humor(μg/ml). Each value shows the mean value ± standard deviation (4samples). * shows the significance p<0.05 against the control group bythe student- t test.

[0029]FIG. 2 is a graph showing the time course of concentration ofcarteolol hydrochloride in cornea after the instillation of the eye drop(containing 2 w/v % carteolol hydrochloride) of Example 20 in TestExample 2. The horizontal axis shows the time (hour) and the verticalaxis shows the concentration of carteolol hydrochloride in cornea(μg/g). Each value shows the mean value ± standard deviation (4samples). The black circles show the case that the eye drop of Example20 is instilled and the black squares show the case the eye dropprepared by omitting sorbic acid from the components in Example 20. **shows the significance p<0.01 and * shows p<0.05, against the controlgroup by the student- t test.

[0030]FIG. 3 is a graph showing the time course of concentration ofcarteolol hydrochloride in aqueos humor after the instillation of theeye drop (containing 2 w/v % carteolol hydrochloride) of Example 20 inTest Example 2. The horizontal axis shows the time (hour) and thevertical axis shows the concentration of carteolol hydrochloride inaqueous humor (μg/ml). Each value shows the mean value ± standarddeviation (4 samples). The black circles show the case that the eye dropof Example 20 is instilled and the black squares show the case the eyedrop prepared by omitting sorbic acid from the components in Example 20.** shows the significance p<0.01 and * shows p<0.05, against the controlgroup by the student- t test.

[0031]FIG. 4 is a graph showing the time course of concentration ofcarteolol hydrochloride in iris and ciliary body after the instillationof the eye drop (containing 2 w/v % carteolol hydrochloride) of Example20 in Test Example 2. The horizontal axis shows the time (hour) and thevertical axis shows the concentration of carteolol hydrochloride in irisand ciliary body (μg/g). Each value shows the mean value±standarddeviation (4 samples). The black circles show the case that the eye dropof Example 20 is instilled and the black squares show the case the eyedrop prepared by omitting sorbic acid from the components in Example 20.** shows the significance p<0.01 and * shows p<0.05, against the controlgroup by the student- t test.

[0032]FIG. 5 is a graph showing the time course of concentration oftimolol in aqueous humor after the instillation of the eye drop(containing 0.68 w/v % timolol maleate) of Example 8 in Test Example 3.The horizontal axis shows the time (hour) and the vertical axis showsthe concentration of timolol in aqueous humor (μg/ml). Each value showsthe mean value±standard deviation (5 samples). The black circles showthe case that the eye drop of Example 8 is instilled and the blacksquares show the case the eye drop prepared by omitting sorbic acid fromthe components in Example 8. ** shows the significance p<0.01 and *shows p<0.05, against the control group by the student- t test.

[0033]FIG. 6 is a graph showing the time course of concentration oftimolol in cornea after the instillation of the eye drop (containing0.68 w/v % timolol maleate) of Example 8 in Test Example 3. Thehorizontal axis shows the time (hour) and the vertical axis shows theconcentration of timolol in cornea (μg/g). Each value shows the meanvalue ± standard deviation (5 samples). The black circles show the casethat the eye drop of Example 8 is instilled and the black squares showthe case the eye drop prepared by omitting sorbic acid from thecomponents in Example 8. ** shows the significance p<0.01 and * showsp<0.05, against the control group by the student-t test.

[0034]FIG. 7 is a graph showing the time course of concentraton oftimolol in iris and ciliary body after the instillation of the eye drop(containing 0.68 w/v % timolol maleate) of Example 8 in Test Example 3.The horizontal axis shows the time (hour) and the vertical axis showsthe concentration of timolol in iris and ciliary body (μg/g). Each valueshows the mean value ± standard deviation (5 samples). The black circlesand the black squares show each case that the eye drop of Example 8 orthe eye drop of Example 8 without sorbic acid is instilled,respectively. ** shows the significance p<0.01 and * shows p<0.05,against the control group by the student- t test.

[0035]FIG. 8 is a graph showing the amount of carteolol hydrochloridepenetrated in aqueous humor at the time of 1 hour after the instillationof the eye drop (containing 2 w/v % carteolol hydrochloride) of Examples2, 17, 18 and 19 in Test Example 4. The horizontal axis shows the testgroup and the vertical axis shows the concentration of carteololhydrochloride in aqueous humor (μg/ml). Each value shows the meanvalue±standard deviation (3 samples). * shows the significance p<0.05against the control group by the student- t test.

BEST MODE FOR CARRYING OUT THE INVENTION

[0036] The present invention is further explained by the following TestExamples and Examples, but not limited thereto.

[0037] Example 1

[0038] Eye Drop

[0039] According to the usual method, a carteolol hydrochloride eye dropcomprising the following components was prepared. Carteololhydrochloride  2.0 g Sorbic acid  0.3 g Sodium dihydrogen phosphate  0.1g Sodium chloride  0.7 g Benzalkonium chloride 0.005 g Sodium hydroxideq.s. Sterilized pure water total 100 ml pH 7.0

[0040] Example 2

[0041] According to the usual method, a carteolol hydrochloride eye dropcomprising the following components was prepared. Carteololhydrochloride  2.0 g Sorbic acid  0.3 g Sodium dihydrogen phosphate  0.1g Sodium chloride  0.43 g Benzalkonium chloride 0.005 g Sodium hydroxideq.s. Sterilized pure water total 100 ml pH 7.0

[0042] Example 3

[0043] According to the usual method, a carteolol hydrochloride eye dropcomprising the following components was prepared. Carteololhydrochloride 1.0 g Sorbic acid 0.3 g Sodium dihydrogen phosphate 0.1 gSodium chloride 0.53 g Benzalkonium chloride 0.005 g Sodium hydroxideq.s. Sterilized pure water total 100 ml pH 6.5

[0044] Example 4

[0045] According to the usual method, a carteolol hydrochloride eye dropcomprising the following components was prepared. Carteololhydrochloride  2.0 g Sorbic acid  0.15 g Sodium dihydrogen phosphate 0.1 g Sodium chloride  0.47 g Benzalkonium chloride 0.005 g Sodiumhydroxide q.s. Sterilized pure water total 100 ml pH 6.5

[0046] Example 5

[0047] According to the usual method, a carteolol hydrochloride eye dropcomprising the following components was prepared. Carteololhydrochloride  2.0 g Sorbic acid  0.51 g Sodium dihydrogen phosphate 0.1 g Sodium chloride  0.29 g Benzalkonium chloride 0.005 g Sodiumhydroxide q.s. Sterilized pure water total 100 ml pH 7.0

[0048] Example 6

[0049] According to the usual method, a carteolol hydrochloride eye dropcomprising the following components was prepared. Carteololhydrochloride  0.5 g Sorbic acid  0.17 g Sodium dihydrogen phosphate 0.1 g Sodium chloride  0.16 g Benzalkonium chloride 0.005 g Sodiumhydroxide q.s. Sterilized pure water total 100 ml pH 7.0

[0050] Example 7

[0051] According to the usual method, a carteolol hydrochloride eye dropcomprising the following components was prepared. Carteololhydrochloride  2.0 g Sorbic acid  1.36 g Sodium dihydrogen phosphate 0.1 g Benzalkonium chloride 0.005 g Sodium hydroxide q.s. Sterilizedpure water total 100 ml pH 7.0

[0052] Example 8

[0053] According to the usual method, a timolol maleate eye dropcomprising the following components was prepared. Timolol maleate  0.68g Sorbic acid  0.35 g Sodium dihydrogen phosphate  0.1 g Sodium chloride 0.56 g Benzalkonium chloride 0.005 g Sodium hydroxide q.s. Sterilizedpure water total 100 ml pH 7.0

[0054] Example 9

[0055] According to the usual method, a timolol maleate eye dropcomprising the following components was prepared. Timolol maleate  0.68g Sorbic acid 0.046 g Sodium dihydrogen phosphate  0.1 g Sodium chloride 0.7 g Benzalkonium chloride 0.005 g Sodium hydroxide q.s. Sterilizedpure water total 100 ml pH 6.5

[0056] Example 10

[0057] According to the usual method, a timolol maleate eye dropcomprising the following components was prepared. Timolol maleate  0.68g Sorbic acid  0.18 g Sodium dihydrogen phosphate  0.1 g Sodium chloride 0.63 g Benzalkonium chloride 0.005 g Sodium hydroxide q.s. Sterilizedpure water total 100 ml pH 6.5

[0058] Example 11

[0059] According to the usual method, a timolol maleate eye dropcomprising the following components was prepared. Timolol maleate 0.34 gSorbic acid 0.35 g Sodium dihydrogen phosphate 0.1 g Sodium chloride0.37 g

[0060] Example 12

[0061] According to the usual method, a timolol maleate eye dropcomprising the following components was prepared. Timolol maleate 0.68 gSorbic acid 1.76 g Sodium dihydrogen phosphate 0.1 g Benzalkoniumchloride 0.005 g Sodium hydroxide q.s. Sterilized pure water total 100ml pH 7.0

[0062] Example 13

[0063] According to the usual method, a betaxolol hydrochloride eye dropcomprising the following components was prepared. Betaxololhydrochloride 0.56 g Sorbic acid 0.91 g Sodium dihydrogen phosphate 0.1g Benzalkonium chloride 0.005 g Sodium hydroxide q.s. Sterilized purewater total 100 ml pH 7.0

[0064] Example 14

[0065] According to the usual method, a betaxolol hydrochloride eye dropcomprising the following components was prepared. Betaxololhydrochloride 0.56 g Sorbic acid 0.37 g Sodium dihydrogen phosphate 0.1g Sodium chloride 0.56 g Benzalkonium chloride 0.005 g Sodium hydroxideq.s. Sterilized pure water total 100 ml pH 7.0

[0066] Example 15

[0067] According to the usual method, a betaxolol hydrochloride eye dropcomprising the following components was prepared. Betaxololhydrochloride 0.56 g Sorbic acid 0.18 g Sodium dihydrogen phosphate 0.1g Sodium chloride 0.65 g Benzalkonium chloride 0.005 g Sodium hydroxideq.s. Sterilized pure water total 100 ml pH 7.0

[0068] Example 16

[0069] According to the usual method, a betaxolol hydrochloride eye dropcomprising the following components was prepared. Betaxololhydrochloride 0.56 g Sorbic acid 0.09 g Sodium dihydrogen phosphate 0.1g Sodium chloride 0.7 g Benzalkonium chloride 0.005 g Sodium hydroxideq.s. Sterilized pure water total 100 ml pH 7.0

[0070] Example 17

[0071] According to the usual method, a carteolol hydrochloride eye dropcomprising the following components was prepared. Carteololhydrochloride 2.0 g Caproic acid 0.31 g Sodium dihydrogen phosphate 0.1g Sodium chloride 0.41 g Benzalkonium chloride 0.005 g Sodium hydroxideq.s. Sterilized pure water total 100 ml pH 7.0

[0072] Example 18

[0073] According to the usual method, a carteolol hydrochloride eye dropcomprising the following components was prepared. Carteololhydrochloride 2.0 g Crotonic acid 0.23 g Sodium dihydrogen phosphate 0.1g Sodium chloride 0.41 g Benzalkonium chloride 0.005 g Sodium hydroxideq.s. Sterilized pure water total 100 ml pH 7.0

[0074] Example 19

[0075] According to the usual method, a carteolol hydrochloride eye dropcomprising the following components was prepared. Carteololhydrochloride 2.0 g Butyric acid 0.24 g Sodium dihydrogen phosphate 0.1g Sodium chloride 0.4 g Benzalkonium chloride 0.005 g Sodium hydroxideq.s. Sterilized pure water total 100 ml pH 7.0

[0076] Example 20

[0077] Eye Drop

[0078] According to the usual method, a carteolol hydrochloride eye dropcomprising the following components was prepared. Carteololhydrochloride 2.0 g Sorbic acid 0.3 g Sodium dihydrogen phosphate 0.1 gSodium chloride 0.7 g Sodium hydroxide q.s. Sterilized pure water total100 ml pH 7.0

TEST EXAMPLE 1

[0079] Test of the Penetration of Carteolol Hydrochloride into Eye ofArbino Rabbit

[0080] (Experimental method)

[0081] 50 μl of the eye drop of Example 1 was instilled once to the malearbino rabbit. The rabbit was slaughtered to withdraw the aqueous humorafter 1 hour of the instillation, then the concentration of carteololhydrochloride in aqueous humor was measured. As the control, an eye dropprepared by omitting sorbic acid from the components of Example 1 wasinstilled to the rabbit. In the same manner as above, the concentrationof carteolol hydrochloride in aqueous humor was measured.

[0082] (Results of the experiment)

[0083] The results are shown in FIG. 1. The amount of carteololhydrochloride in aqueous humor was 3 times higher for the eye dropcontaining sorbic acid than that of the eye drop without sorbic acid.

[0084] The above results show that the penetration of carteololhydrochloride into the eye is promoted by incorporating sorbic acid inthe eye drop containing carteolol hydrochloride.

TEST EXAMPLE 2

[0085] Test of the Retention of Carteolol Hydrochloride in the OcularTissues of the Pigmented Rabbit

[0086] (Experimental method)

[0087] 50 μl of the eye drop of Example 20 was instilled once to themale pigmented Dutch rabbit. Each rabbit was slaughtered to withdraw theaqueous humor at post-instillation times of 0.5, 1, 2, 4, 6, 12 and 24hours, then cornea and iris-ciliary body were excised to measure theconcentration of carteolol hydrochloride in cornea, aqueous humor andiris-ciliary body. As the control, an eye drop prepared by omittingsorbic acid from the components of Example 20 was instilled to therabbit. In the same manner as above, the concentration of carteololhydrochloride in cornea, aqueous humor and iris-ciliary body wasmeasured.

[0088] (Results of the experiment)

[0089] (1) The time course of concentration of carteolol hydrochloridein cornea is shown in FIG. 2. The eye drop containing sorbic acid gavethe delay of elimination of carteolol hydrochloride from the cornea andthe high concentration thereof at every time as compared with the eyedrop without sorbic acid used as the control. The area under the curve(AUC) for drug concentration-time profiles in cornea was 1.9 time higherfor the eye drop containing sorbic acid than that of the control.

[0090] (2) The time course of concentration of carteolol hydrochloridein aqueous humor is shown in FIG. 3. Similarly with the case of cornea,the eye drop containing sorbic acid gave the delay of elimination ofcarteolol hydrochloride in aqueous humor and the high concentrationthereof at every time as compared with the eye drop without sorbic acidused as the control. The area under the curve for the drugconcentration-time profiles in aqueous humor for the eye drop containingsorbic acid was about 2.1 times higher than that of the control.

[0091] (3) The time course of the concentration of carteololhydrochloride in iris-ciliary body is shown in FIG. 4. The eye dropcontaining sorbic acid gave high concentration of carteololhydrochloride in the iris-ciliary body as compared with that of the eyedrop without sorbic acid used as the control. The area under the curvefor the drug concentration-time profiles in the iris-ciliary body forthe eye drop containing sorbic acid was about 3.6 times higher than thatof the control.

[0092] The above results show that the retention period of carteololhydrochloride in the ocular tissues is improved because carteololhydrochloride in the intraocular tissues is kept at the highconcentration and because the elimination of carteolol hydrochloride inthe ocular tissues is delayed by incorporating sorbic acid in the eyedrop containing carteolol hydrochloride.

TEST EXAMPLE 3

[0093] Test of the Penetration of Timolol Maleate into the Eye of theArbino Rabbit

[0094] (Experimental method)

[0095] 50 μl of the eye drop of Example 8 was instilled once to the malearbino rabbit. Each rabbit was slaughtered to withdraw the aqueous humorat post-instillation of 15, 30 minutes, 1 and 3 hours, then cornea andiris-ciliary body were excised to measure the concentration of timololmaleate in aqueous humor, cornea and iris-ciliary body. As the control,0.5% Timoptol® (produced by Banyu Pharmacetical Co., Ltd.) was instilledto the rabbit. In the same manner as above, the concentration of timololmaleate in aqueous humor, cornea and iris-ciliary body was measured.

[0096] (Results of the experiment)

[0097] (1) The concentration-time profiles of timolol in aqueous humoris shown in FIG. 5. The concentration of timolol in aqueous humor ateach post-instillation time of 15 minutes and 30 minutes was about 3.6times higher for the eye drop containing sorbic acid and about 3.8 timeshigher, respectively, than that of the control. Also, the concentrationof timolol for the eye drop containing sorbic acid was higher at everytime and the area under the curve (AUC) for the drug concentration-timeprofiles in aqueous humor was about 2.2 times higher than that of thecontrol.

[0098] (2) The drug concentration-time profiles of timolol in cornea isshown in FIG. 6. The concentration of timolol in cornea at eachpost-instillation time of 15 minutes and 30 minutes was 2.9 times higherfor the eye drop containing sorbic acid and about 3.6 times higher,respectively than that of the control. Also, similarly with the drugconcentration in aqueous humor, the concentration of timolol in corneafor the eye drop containing sorbic acid was kept at higher concentrationat every time and the area under the curve (AUC) for the drugconcentration-time profiles in cornea was about 2.4 times higher thanthat of the control.

[0099] (3) The drug concentration-time profiles of timolol iniris-ciliary body is shown in FIG. 7. The concentration of timolol iniris-ciliary body at each post-instillation times of 15 minutes and 30minutes for the eye drop containing sorbic acid was about 3.1 timeshigher and about 3.4 times higher, respectively, than that of thecontrol. Also, similarly with the drug concentrations in aqueous humorand cornea, the concentration of timolol in iris-ciliary body was higherat every time and the area under the curve (AUC) for the drugconcentration-time profiles in iris-ciliary body was about 2.1 timeshigher for the eye drop containing sorbic acid than that of the control.

[0100] The above results show that the penetration of timolol maleateinto aqueous humor, cornea and iris-ciliary body is promoted immediatelyafter the instillation by incorporating sorbic acid in the eye dropcontaining timolol maleate. It is also shown that the retention oftimolol maleate in the ocular tissues is improved because theconcentration of timolol maleate in the ocular tissues kept at thehigher concentration level at each time than that of 0.5% Timoptol®(produced by Banyu Pharmaceutical Co., Ltd.) used as the control.

TEST EXAMPLE 4

[0101] Effect of the Saturated or Unsaturated Fatty Acid on thePenetration of Carteolol Hydrochloride

[0102] (Experimental method)

[0103] 50 μl of each eye drop of Example 2 (containing sorbic acid as anunsaturated fatty acid), Example 17 (containing caproic acid as asaturated fatty acid), Example 18 (containing crotonic acid as anunsaturated fatty acid) and Example 19 (containing butyric acid as asaturated fatty acid) was instilled once to each male arbino rabbit.Each rabbit was slaughtered to withdraw aqueous humor atpost-instillation time of 1 hour, then the concentration of carteololhydrochloride in aqueous humor was measured. As the control, an eye dropprepared by omitting sorbic acid from the components of Example 2 wasinstilled to the rabbit. In the same manner as above, the concentrationof carteolol hydrochloride in aqueous humor was measured.

[0104] (Results of the experiment)

[0105] The results are shown in FIG. 8. The concentration of cartololhydrochloride in aqueous humor at post-instillation time of 1 hour wasabout 2.1 times higher for the eye drop containing sorbic acid, about2.8 times higher for the eye drop containing caproic acid, about 1.8time higher for the eye drop containing crotoic acid and about 2 timeshigher for the eye drop containing butyric acid respectively than thatof the control without the fatty acid.

[0106] The above results show that the penetration of carteololhydrochloride into the eye is promoted by incorporating the saturated orunsaturated fatty acid in the eye drop containing carteololhydrochloride.

TEST EXAMPLE 5

[0107] Effect of Sorbic Acid on the Penetration of BetaxololHydrochloride

[0108] (Experimental method)

[0109] 50 μl of each eye drop of Example 13 (betaxololhydrochloride:sorbic acid=1:2, mole ratio) and Example 14 (betaxololhydrochloride:sorbic acid=1:5, mole ratio) was instilled to each malearbino rabbit, respectively. Each rabbit was slaughtered to withdrawaqueous humor at post-instillation time of 1 hour, then theconcentration of betaxolol hydrochloride in aqueous humor was measured.As the control, an eye drop prepared by omitting sorbic acid in Example13 was instilled to the rabbit in the same manner as above, theconcentration of betaxolol hydrochloride in aqueous humor was measured.

[0110] (Results of the experiment)

[0111] The concentration of betaxolol hydrochloride in aqueous humor atpost-instillation time of 1 hour was 2.57±1.45 μg/ml (3 samples) for theeye drop of Example 13 and 2.89±0.75 μg/ml (4 samples) for the eye dropof Example 14, were about 2.2 times higher and about 2.5 times higher,respectively than 1.16±0.45 μg/ml (4 samples) for the eye drop withoutsorbic acid used as the control. The results show that the penetrationof betaxolol hydrochloride into the eye is promoted by incorporatingsorbic acid in the eye drop containing betaxolol hydrochloride.

INDUSTRIAL APPLICABILITY

[0112] Because the eye drop of the present invention promotes thepenetration of the β-blocker into the eye and improves the retention ofthe β-blocker in the ocular tissues, the times of the instillation canbe reduced and the apprehension concerning the frequent instillationscan be avoided and therefore, it is useful for the eye drop. Also, it isuseful for eye drop giving the sufficient effect for lowering theintraocular pressure even when the content of the β-blocker is reduced.

[0113] The present invention is based on Japanese Patent ApplicationsNo. 9/302802 and No. 10/250009, and contains the whole contents thereofin the present specification.

1. An eye drop comprising a β-blocker and a C₃-C₇ fatty acid or the saltthereof.
 2. The eye drop according to claim 1 , wherein the β-blocker iscarteolol or the salt thereof.
 3. The eye drop according to claim 1 ,wherein the β-blocker is timolol or the salt thereof.
 4. The eye dropaccording to claim 1 , wherein the β-blocker is betaxolol or the saltthereof.
 5. The eye drop according to one of claims 1 to 4 , wherein theC₃-C₇ fatty acid is an unsaturated fatty acid.
 6. The eye drop accordingto one of claims 1 to 5 , wherein the C₃-C₇ fatty acid is a C₆unsaturated fatty acid.
 7. The eye drop according to claim 6 , whereinthe C₆ unsaturated fatty acid is sorbic acid.
 8. A method for promotingthe penetration of a β-blocker into the eye and for improving theretention of the β-blocker in the ocular tissues which comprisesincorporating a C₃-C₇ fatty acid or the salt thereof into an eye dropcontaining the β-blocker.